1. Field of the Invention
The present invention relates generally to the field of immunology. More specifically, it relates to dendritic cell binding proteins and uses thereof.
2. Description of the Related Art
Dendritic cells (DCs) are a complex, heterogeneous group of multifunctional antigen presenting cells. Dendritic cells comprise an essential component of the immune system. The role of these cells has been repeatedly highlighted in cancer and infectious diseases. Recently, there have been great insights into the origins of dendritic cell subsets and their modulation by distinct cytokines of neighboring cells.
Dendritic cells differentiate into at least three pathways: myeloid (MDC), plasmacytoid (LDC), and Langerhans cell (LC) (1-7). Progenitors of myeloid dendritic cells in bone marrow migrate via the blood stream and home to the peripheral tissues ready to confront invading pathogens. In such environments, dendritic cells ingest antigens via several mechanisms including phagocytosis and receptor-mediated endocytosis. Langerhans cells phagocytose, process, and present protein antigens to T cells. Antigenic infectious agents including vaccines induce pro-inflammatory cytokines, e.g., TNF-a. These cytokines promote Langerhans cell maturation and migration to plasmacytoid organs where they home to the T cell rich area.
Langerhans cells undergo phenotypic and functional changes during their maturation and migration. These cells, which are now loaded with antigenic peptides on MHC class II, down-regulate CD1a, CCR6, and E-cadherin, and lose the capacity to capture foreign antigens. Human CD14+ progenitor dendritic cells cultured in GM-CSF+IL-4 are equivalent to interstitial dendritic cells, i.e., dermal dendritic cells, and express CD1a, CD64 and Factor IIIa. By contrast, monocytes cultured with M-CSF convert to a macrophage phenotype. These myeloid dendritic cells may home within plasmacytoid follicles, where they reside as germinal center dendritic cells. In this area, germinal center dendritic cells establish the contact between T- and B-cells, which may lead to the stimulation of an active immune response.
Dendritic cells present processed antigenic peptides on MHC class II molecules to CD4+ T cells, which will be activated in conjunction with co-stimulatory signals such as CD40 and CD86 delivered from dendritic cells in plasmacytoid organs. Several receptors and their ligands are involved in the T cell/dendritic cell dialogue, such as CD40/CD40L. For instance, up-regulation of CD40L on T cells facilitates dendritic cell maturation. Activated dendritic cells then release cytokines such as IL-12, which modulate and stimulate the production of interferon (IFN)-γ from T cells. In situ, activated dendritic cells can prime naïve CD8+ T cells, or they undergo apoptosis. Activated T cells, via activated adhesion molecules, migrate to the area of the B-cell follicles. There they interact with naïve antigen-specific B cells. T- and B-cell interaction results in the clonal expansion of B cells, which takes place in the plasma foci of the T cell rich area and in the germinal centers. T- and B-cell dialogue in the germinal center might be influenced by germinal center dendritic cells and follicular dendritic cells.
Peyer's patch dendritic cells are critical components of mucosal-associated plasmacytoid tissue (MALT). The Peyer's patch is the primary mucosal site for antigen processing in the intestine. Recent in vivo studies provide evidence that dendritic cell network in the subepithelial dome of Peyer's patch is a critical component in the uptake and processing of luminal antigens. Such uptake may occur by endocytosis or by phagocytosis after passage of antigen through M cells. The dendritic cells then present the processed antigen to CD4+ or CD8+ T cells in the subepithelial dome, or after maturation and migration, to the interfollicular regions where antigen is presented to CD4+ or CD8+ T cells. In this regard, immunohistologic analysis of dendritic cell subsets including LCs in Peyer's patch has revealed that the unique microanatomical localization of dendritic cell subsets enables them to regulate specific T- and B-cell responses in vivo.
To date, most studies of dendritic cells in oral mucosa have focused on immature dendritic cells (Langerhans cells). Immature dendritic cell subsets have been observed to increase in number in oral mucosa affected by gingivitis-periodontitis, oral lichen planus, histocytosis X, oral candidiasis, and contact hypersensitivity responses to dental material and oral cancer. Most often, the distribution of dendritic cells in oral mucosa parallels that of T cells, suggesting that these dendritic cells are engaged in antigen presentation in situ.
The human immunodeficiency virus (HIV) epidemic has killed more than 24 million people and more than 40 million individuals are infected with HIV as cited in UNAIDS, 2001. Mucosal cells that cover all the cavities of the body including mouth are portals of HIV entry. Specific protective effector cells are incompletely characterized, but it is likely that immunity to chronic infection is mediated primarily by cellular defenses, including HIV-specific CTLs. A safe and effective vaccine for HIV that can be prepared easily in large quantities and delivered on a global scale is needed urgently to halt this epidemic.
The hypermutability of the HIV genome is a major challenge for vaccine development. Purified subunit vaccines rely heavily on the antibody response for protection, and this has been recognized for some time to be a severe limitation for vaccines against viruses, especially MV. Thus, several research groups have attempted to prepare vaccines that induce specific cellular immune responses. This strategy deals with viral gene products that are not exposed to antibody and thus exhibit less variability than the envelope glycoprotein. For HIV, novel recombinant viruses and pure DNA vaccines induce weak antibody responses. Thus, promising vaccine protocols entail priming with DNA or virus and a boosting with purified envelope glycoprotein.
Hepatitis C virus (HCV), a member of the Flaviviridae, is a positive-sense, single-stranded RNA with genome size of 9.4 kb, identified in 1989 as the major etiologic agent of non-A, non-B hepatitis. Hepatitis C virus infects not only hepatocytes, but may also infect lymphocytes and monocytes. A disturbing feature of hepatitis C virus is its long-term persistence in the host, followed by chronic liver disease and the associated possibilities of hepatocellular carcinoma, cryoglobulinemia, and autoimmunity. The current therapy for hepatitis C virus is type I interferon plus ribavirin in combination. However, less than 41% of patients respond.
DC as a critical vector for vaccine strategy induce potent antigen-specific immunity in various settings including human clinical trials (8-10). Optimal means of delivering immunogenic antigen to DC remain undefined, but current immunotherapy relies largely on ex vivo methods. While useful to demonstrate proof-of-concept, ex vivo growth of DC is logistically difficult (24). While DC based immunotherapy highlighted its critical role in inducing antigen specific immunity, however at present, DC-targeting strategies are hampered by lack of DC-specific target molecules.
The prior art is deficient in the lack of novel dendritic cell binding peptides and uses thereof. The present invention fulfills this long-standing need and desire in the art.